ABSTRACT Diabetic neuropathy (DN) is the most common chronic complication of diabetes, affecting up to 50% of individuals with type 1 diabetes (T1DM). DN is a progressive disease, leading to severe morbidity and staggering health care costs ($22 billion/year www.diabetes.org). Patients experience poor quality of life due to pain, loss of sensation leading to poor balance, falls and eventual foot deformities with high rates of ulcerations and amputations. While not as commonly diagnosed as DN, cardiovascular autonomic neuropathy (CAN) carries equal morbidity with patients experiencing orthostasis, arrhythmias and premature death. Evidence for an important role of low-grade inflammation in the pathogenesis of DN and CAN is emerging from both experimental and clinical studies. We recently completed a series of microarray analyses of sural nerve biopsies from subjects with stable versus progressive DN and discovered a highly significant increase in the expression of ?inflammatory response? genes in subjects with progressive DN..Salsalate is highly effective antiinflammatory therapy, with a large margin of safety and low cost. In a prior proof of concept pilot study (R03 DK 094499), we obtained the IND (IND 113650) for the use of salsalate and completed clinical and safety assessments in 8 subjects with T1DM and DN, treated with 3 gram/day salsalate for 3 months, with evidence of early clinical efficacy and drug safety. Our long-term goal is to identify mechanism based therapies for the treatment of DN and CAN. The objective here is to determine if salsalate is an effective and safe therapy for DN and CAN. Our central hypothesis is that inflammation has a role in the development and progression of DN and CAN and that blocking inflammation with salsalate can positively affect disease progression. The rationale for the proposed research is that a pilot clinical trial of salsalate therapy will: 1) test the role of inflammation in DN and CAN, 2) allow for biomarker development for both disorders, and 3) provide the justification for a large scale clinical trial of salsalate in the treatment of DN and CAN. We plan to test our central hypothesis, and thereby accomplish the objective of this application, by pursuing two specific aims: Aim 1: Examine the therapeutic efficacy of 3 gram/day salsalate for 12 months on measures of DN and CAN in subjects with T1DM and mild DN Aim 2: Determine the safety profile of 3 gram/day salsalate in patients with T1DM and mild DN